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|Ref Type||Journal Article|
|Authors||Plummer R, Dua D, Cresti N, Drew Y, Stephens P, Foegh M, Knudsen S, Sachdev P, Mistry BM, Dixit V, McGonigle S, Hall N, Matijevic M, McGrath S, Sarker D|
|Title||First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.|
|Journal||British journal of cancer|
|Date||2020 Jun 11|
|Abstract Text||This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing.The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.www.ClinicalTrials.gov code: NCT01618136.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|E7449||2X-121||PARP Inhibitor (Pan) 22 Tankyrase Inhibitor 10||E7449 (2X-121) binds to and inhibits PARP1 and PARP2, as well as TNKS1 and TNKS2, potentially resulting in increased sensitivity to DNA damaging agents and decreased growth of tumor cells with defective DNA damage repair (PMID: 26513298, PMID: 32523090).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||E7449||Phase I||Actionable||In a Phase I trial, E7449 treatment demonstrated safety and resulted in an overall response rate of 4.9% (2/41, partial responses) and stable disease in 31.7% (13/41) of patients with advanced solid tumors, including stable disease lasting greater than 23 weeks in 8 patients (PMID: 32523090; NCT01618136).||32523090|